This invention relates to prostacyclin derivatives and to processes for preparing them.
The prostacyclins are a group of organic compounds, including for example prostacyclin itself, also named as prostaglandin I.sub.2 (PGI.sub.2), represented by formula 1. Prostacyclin is (5Z)-9-deoxy-6,9.alpha.-epoxy-.DELTA.5-PGF.sub.1.alpha. (using prostaglandin nomenclature) or (5Z, 9.alpha., 11.alpha., 13E, 15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid. The atom numbering of the carbon skeleton is shown in that formula. Also defined by this structure are the absolute configurations (5Z, 8R, 9S, 11R, 12R, 13E, and 15S) for the potentially isomeric centers of this molecule.
For background on prostacyclin, see for example R. A. Johnson et al., Prostaglandins 12, 915-928 (1976) and R. A. Johnson et al., J. Am. Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity, the references cited therein. For analogs of prostacyclin, see, for example, J. Fried et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203, K. C. Nicolaou et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson, J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima et al., Tetra. Letters, 1978, 3743-3746. Regarding the nomenclature for analogs of PGI.sub.2, see R. A. Johnson et al., Prostaglandins 15, 737-740 (1978).
Prostacyclins are related to prostaglandins which are in turn related to prostanoic acid which has the structure and atom numbering of formula 2. There is extensive literature on prostaglandins, but for background see for example Bergstrom et al., Pharmacol. Rev. 20, 1 (1968). PGF.sub.2.alpha. is represented by formula 3.
As drawn herein the formulas represent a specific optically active isomer having the same absolute configuration as PGE.sub.1 obtained from mammalian tissues.
In the formulas, broken line attachments to the cyclopentane ring or side chain indicate substituents in alpha configuration, i.e. below the plane of the ring or side chain. Heavy solid line attachments indicate substituents in beta configuration, i.e. above the plane. With respect to "R" and "S" usage, see R. S. Cahn, J. Chem. Ed. 41, 116 (1964). As to "Z" and "E" nomenclature for stereoisomerism about a double bond see J. E. Blackwood et al., J. Am. Chem. Soc. 90, 509 (1968).